scholarly journals Cellular Senescence: Mechanisms and Therapeutic Potential

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1769
Author(s):  
Zehuan Liao ◽  
Han Lin Yeo ◽  
Siaw Wen Wong ◽  
Yan Zhao
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Biological Process ◽  
Therapeutic Potential ◽  
Biological Processes ◽  
Limb Patterning ◽  
Cycle Arrest ◽  
Major Interest ◽  
Secretory Phenotype

Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes—both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regarding the identification of unique biomarkers of senescent cells. This review attempts to provide a comprehensive understanding of the diverse literature on senescence, and discuss the knowledge we have on senescence thus far.

scholarly journals Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype

2021 ◽  
Vol 9 ◽  
Author(s):  
Ruchi Kumari ◽  
Parmjit Jat
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Growth Arrest ◽  
Dependent Manner ◽  
Tissue Repair And Regeneration ◽  
Cycle Arrest ◽  
Age Related ◽  
Secretory Phenotype

Cellular senescence is a stable cell cycle arrest that can be triggered in normal cells in response to various intrinsic and extrinsic stimuli, as well as developmental signals. Senescence is considered to be a highly dynamic, multi-step process, during which the properties of senescent cells continuously evolve and diversify in a context dependent manner. It is associated with multiple cellular and molecular changes and distinct phenotypic alterations, including a stable proliferation arrest unresponsive to mitogenic stimuli. Senescent cells remain viable, have alterations in metabolic activity and undergo dramatic changes in gene expression and develop a complex senescence-associated secretory phenotype. Cellular senescence can compromise tissue repair and regeneration, thereby contributing toward aging. Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span. Senescence can also act as a potent anti-tumor mechanism, by preventing proliferation of potentially cancerous cells. It is a cellular program which acts as a double-edged sword, with both beneficial and detrimental effects on the health of the organism, and considered to be an example of evolutionary antagonistic pleiotropy. Activation of the p53/p21WAF1/CIP1 and p16INK4A/pRB tumor suppressor pathways play a central role in regulating senescence. Several other pathways have recently been implicated in mediating senescence and the senescent phenotype. Herein we review the molecular mechanisms that underlie cellular senescence and the senescence associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.

scholarly journals Jumonji C Demethylases in Cellular Senescence

Genes ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 33 ◽  
Author(s):  
Kelly E. Leon ◽  
Katherine M. Aird
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Histone Methylation ◽  
Epigenetic Changes ◽  
Cycle Arrest ◽  
Expression Of Genes ◽  
Jmjc Domain ◽  
Secretory Phenotype

Senescence is a stable cell cycle arrest that is either tumor suppressive or tumor promoting depending on context. Epigenetic changes such as histone methylation are known to affect both the induction and suppression of senescence by altering expression of genes that regulate the cell cycle and the senescence-associated secretory phenotype. A conserved group of proteins containing a Jumonji C (JmjC) domain alter chromatin state, and therefore gene expression, by demethylating histones. Here, we will discuss what is currently known about JmjC demethylases in the induction of senescence, and how these enzymes suppress senescence to contribute to tumorigenesis.

scholarly journals Jumonji C Demethylases in Cellular Senescence

2018 ◽  
Author(s):  
Kelly E. Leon ◽  
Katherine M. Aird
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Histone Methylation ◽  
Epigenetic Changes ◽  
Cycle Arrest ◽  
Expression Of Genes ◽  
Jmjc Domain ◽  
Secretory Phenotype

Senescence is a stable cell cycle arrest that is either tumor suppressive or tumor promoting depending on context. Epigenetic changes such as histone methylation are known to affect both induction and suppression of senescence by altering expression of genes that regulate the cell cycle and the senescence-associated secretory phenotype. A conserved group of proteins containing a Jumonji C (JmjC) domain alter chromatin state, and therefore gene expression, by demethylating histones. Here, we will discuss what is currently known about JmjC demethylases in induction of senescence and how these enzymes suppress senescence to contribute to tumorigenesis.

scholarly journals Cellular Senescence in Liver Disease and Regeneration

2021 ◽  
Author(s):  
Sofia Ferreira-Gonzalez ◽  
Daniel Rodrigo-Torres ◽  
Victoria L. Gadd ◽  
Stuart J. Forbes
Keyword(s):  
Cell Cycle ◽  
Liver Disease ◽  
Cell Cycle Arrest ◽  
Genomic Instability ◽  
Cellular Senescence ◽  
Cell Populations ◽  
Cycle Arrest ◽  
Relevant Role ◽  
Extent Of Damage

AbstractCellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. The evidence of senescent mechanisms acting on the cell populations of the liver will be described including the role of markers to detect cellular senescence. Overall, this review intends to summarize the role of senescence in liver homeostasis, injury, disease, and regeneration.

scholarly journals Quantitative Model of Cell Cycle Arrest and Cellular Senescence in Primary Human Fibroblasts

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e42150 ◽  
Author(s):  
Sascha Schäuble ◽  
Karolin Klement ◽  
Shiva Marthandan ◽  
Sandra Münch ◽  
Ines Heiland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Human Fibroblasts ◽  
Quantitative Model ◽  
Cycle Arrest

scholarly journals The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype

2018 ◽  
Author(s):  
Priya Hari ◽  
Fraser R. Millar ◽  
Nuria Tarrats ◽  
Jodie Birch ◽  
Curtis J. Rink ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Cycle Arrest ◽  
Secretory Phenotype ◽  
Immune Sensing ◽  
Molecular Patterns ◽  
Innate Immune Sensing

ABSTRACTCellular senescence is a stress response program characterised by a robust cell cycle arrest and the induction of a pro-inflammatory senescence-associated secretory phenotype (SASP) that is triggered through an unknown mechanism. Here, we show that during oncogene-induced senescence (OIS), the Toll-like receptor TLR2 and its partner TLR10 are key mediators of senescence in vitro and in murine models. TLR2 promotes cell cycle arrest by regulating the tumour suppressors p53-p21CIP1, p16INK4a and p15INK4b, and regulates the SASP through the induction of the acute-phase serum amyloids A1 and A2 (A-SAA) that, in turn, function as the damage associated molecular patterns (DAMPs) signalling through TLR2 in OIS. Finally, we found evidence that the cGAS-STING cytosolic DNA sensing pathway primes TLR2 and A-SAA expression in OIS. In summary, we report that innate immune sensing of senescence-associated DAMPs by TLR2 controls the SASP and reinforces the cell cycle arrest program in OIS.

scholarly journals Dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest

Genomics ◽  
2020 ◽  
Vol 112 (2) ◽  
pp. 1309-1317 ◽  
Author(s):  
Zhen Zhao ◽  
Qiongye Dong ◽  
Xuehui Liu ◽  
Lei Wei ◽  
Liyang Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Transcriptome Profiling ◽  
Cycle Arrest

scholarly journals Oncogenic ras and p53 Cooperate To Induce Cellular Senescence

2002 ◽  
Vol 22 (10) ◽  
pp. 3497-3508 ◽  
Author(s):  
Gerardo Ferbeyre ◽  
Elisa de Stanchina ◽  
Athena W. Lin ◽  
Emmanuelle Querido ◽  
Mila E. McCurrach ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Map Kinase ◽  
Cell Cycle Arrest ◽  
Cellular Senescence ◽  
Null Mouse ◽  
P53 Expression ◽  
Oncogenic Ras ◽  
Cycle Arrest ◽  
Murine Fibroblasts ◽  
Mitogen Activated Protein

ABSTRACT Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53val135 ) into p53-null mouse embryonic fibroblasts and examined cell proliferation and senescence in cells expressing p53, oncogenic Ras, or both gene products. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras or activated mek1 with p53 enhanced both p53 levels and activity relative to that observed for p53 alone and produced an irreversible cell cycle arrest that displayed features of cellular senescence. p19ARF was required for this effect, since p53 −/− ARF −/− double-null cells were unable to undergo senescence following coexpression of oncogenic Ras and p53. Although the levels of exogenous p53 achieved in ARF-null cells were relatively low, the stabilizing effects of p19ARF on p53 could not explain the cooperation between oncogenic Ras and p53 in promoting senescence. Hence, enforced p53 expression without oncogenic ras in p53 −/− mdm2 −/− double-null cells produced extremely high p53 levels but did not induce senescence. Taken together, our results indicate that oncogenic activation of the MAP kinase pathway in murine fibroblasts converts p53 into a senescence inducer through both quantitative and qualitative mechanisms.

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